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1.
Chinese Journal of Lung Cancer ; (12): 934-942, 2024.
文章 在 中文 | WPRIM | ID: wpr-1010101

摘要

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
.


Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , ErbB Receptors/metabolism , Immunotherapy , Mutation , B7-H1 Antigen/genetics , Protein Kinase Inhibitors/pharmacology , Tumor Microenvironment
2.
文章 在 中文 | WPRIM | ID: wpr-1007284

摘要

ObjectiveTo explore the clinical features and causative genes of short stature children with unknown etiology, providing evidence for precise clinical diagnosis and treatment. MethodsThe study recruited children with suspected but undiagnosed short stature from the pediatric endocrinology department in our hospital between January 2018 and August 2022. A retrospective analysis was performed on the clinical manifestations, laboratory test and whole exome sequencing (WES) results. Causative genes were classified and analyzed according to different pathogenic mechanisms. ResultsA total of 48 children (30 boys and 18 girls) were enrolled, aged 7.73 ± 3.97 years, with a height standard deviation score ( HtSDS) of -3.63 ± 1.67. Of the patients, 33 (68.8%) suffered from facial anomalies, 31 (64.6%) from skeletal abnormalities, 26 [54.2%, 61.5% of whom born small for gestational age (SGA)] from perinatal abnormalities, 24 [50.0%, 87.5% of whom with growth hormone (GH) peak concentration below normal] from endocrine disorders and 21(43.8%) had a family history of short stature. Laboratory tests showed that GH peak concentration following stimulation test was (9.72 ± 7.25) ng/mL, IGF-1 standard deviation score was -0.82 ± 1.42, the difference between bone age and chronological age was -0.93 ± 1.39 years. Of the 25 cases with mutant genes found by WES, 14 (56.0%) had pathogenic mutation, 6 (24.0%) likely pathogenic mutation, and 5 (20.0%) mutation of uncertain significance. Pathogenic and likely pathogenic variants were identified in 14 genes, including 10 affecting intracellular signaling pathways (PTPN11, RAF1, RIT1, ARID1B, ANKRD11, CSNK2A1, SRCAP, CUL7, SMAD4 and FAM111A) and 4 affecting extracellular matrix (ECM) components or functions (ACAN, FBN1, COL10A1 and COMP). ConclusionsA rare monogenic disease should be considered as the possible etiology for children with severe short stature accompanied by facial anomalies, disproportionate body types, skeletal abnormalities, SGA, GH peak concentration below normal and a family history of short stature. WES played an important role in identifying the monogenic causes of short stature. This study indicated that affecting growth plate cartilage formation through intracellular signaling pathways and ECM components or functions was the main mechanism of causative genes leading to severe short stature in children. Further research may help discover and study new pathogenic variants and gene functions.

3.
International Eye Science ; (12): 53-57, 2024.
文章 在 中文 | WPRIM | ID: wpr-1003505

摘要

The neural crest represents a dynamic population of embryonic stem cells, playing a pivotal role in the development of the eye. Through interactions with the surrounding neuroectoderm, superficial ectoderm and mesoderm, the neural crest contributes to the formation of numerous ocular structures, encompassing the corneal stroma and endothelium, trabecular meshwork, iris stroma, ciliary muscle, vitreous and choroidal vessels, and Müller cells. Aberrant migration and development of neural crest cells within the eye can instigate a complex series of ocular diseases. Such diseases include anterior segment like Axenfeld-Rieger syndrome, Peters anomaly, aniridia, primary congenital glaucoma, and Nail-Patella syndrome. Defects that impact the posterior segment may lead to CHARGE syndrome and Branchio-oculo-facial syndrome. Further, rare neurocristopathies such as Waardenburg syndrome, Treacher-Collins syndrome, and Char syndrome can also present with ocular abnormalities. In this review, we explore the ocular diseases that arise from abnormal neural crest cell development, and delve into the related genes involved in neural crest migration and development. We further discuss how mutations and defects in these genes can precipitate ocular diseases.

4.
文章 在 中文 | WPRIM | ID: wpr-1016367

摘要

@#Objective To examined gene mutations in thymic carcinoma (TC) patients and to explore prognostic correlates and potential targets for therapy. Methods We retrospectively included TC patients in Sichuan Cancer Hospital between January 2015 and Febuary 2021.Whole-exome sequencing was performed on tumor tissues from TC patients and their control peripheral blood samples, and the raw data were subjected to bioinformatics analysis and statistical analysis. Results We finally included 24 TC patients with 16 males and 8 females at a median age of 55 (42-74) years. The highest frequency of single nucleotide mutations in this cohort were in the TTN gene (42%), HSPG2 (29%), and OBSCN (29%). Higher frequency of copy number variations occurred in ZNF276 gene (54%, loss), BEND3 (50%, loss), DHODH (50%, loss), and VAC14 (50%, loss). Microsatellite instability (MSI) phenotype was found in 25% of the patients, and the mean tumor mutation burden (TMB) was 9.86. Conclusion This study is the first comprehensive analysis of the mutation profile of thymic carcinoma in China to date. The mutation frequencies of TTN, OBSCN, and ZNF276 genes were high. The biomarker analysis suggests that patients may benefit from immunotherapy and have a long effective survival.

5.
Afr. J. Clin. Exp. Microbiol ; 25(2): 139-144, 2024. tables
文章 在 英语 | AIM | ID: biblio-1555642

摘要

Background: Hepatitis C virus (HCV) genome undergoes high rate of mutation, which results in generation of genetically diverse HCV isolates. There is paucity of data on mutations in the nonstructural 5b (NS5b) gene of circulating HCV and their implications in the Nigerian population. Here, we identified clinically-important mutations in HCV isolates, which may influence response to therapy and disease prognosis. Methodology: HCV RNA was extracted from a total of 301 blood samples collected from 99 symptomatic treatment-naïve hepatitis patients, 125 HIV-infected individuals and 77 asymptomatic blood donors in Ibadan, Nigeria. The RNA was reverse­transcribed to complimentary DNA and HCV NS5B gene amplified by nested PCR. The amplified products of 42 HCV were sequenced and sequences were aligned with those from GenBank and HCV databases in MEGA 7.0. Nucleotide sequences were translated to amino acids while substitutions in the amino acids were analyzed with reference to H77 prototype strain of HCV. Results: A total of 10 amino acid polymorphisms were observed from the 42 sequenced NS5B gene, with the major clinically-important amino acid mutations being S15G in 28 (66.7%) participants, T7N (24, 57.1%), G61R (23, 54.8%), S54L (22, 52.4%), G89E (14, 33.3%), T79M (12, 28.6%), and T711 (11, 26.2%). Others were Q67R (7, 16.7%), Q47H (7, 16.7%) and S84F (2, 4.8%). S15G/A/V mutations were more predominant in patients with HIV (76.9%, 10/13) followed by patients with clinical hepatitis (75.0%, 12/16) and blood donors (46.1%, 6/13). Q67R and T71I mutations were not predominant in patients with clinical hepatitis as they were detected in only 31.3% (5/16) and 43.8% (7/16) participants respectively, compared to S15G (75.0%, 12/16), S54L (68.8%, 11/16), G61R/E (68.8%, 11/16) and T7N/S (56.3%, 9/16). There was no statistically significant difference in the distribution of each of the 10 amino acid polymorphisms detected within patients with symptomatic clinical hepatitis (x 2=9.311, p=0.409), HIV-infected patients (x 2=13.431, p=0.1440) and asymptomatic blood donors (x 2=3.775, p=0.9256). Similarly, there was no significant difference in the distribution between the 3 categories of the study participants except for T79M mutation, which was significantly higher in HIV-infected patients (61.5%, 8/13) compared to patients with clinical hepatitis (18.8%, 3/16) and asymptomatic blood donors (7.7%, 1/13) (x 2=10.456, p=0.0054). Conclusion: Mutations in the NS5B gene could be associated with worse prognosis of the disease or antiviral failure due to viral resistance in patients undergoing therapy. The absence of Q47H mutations in majority of the study participants in our study implies that they will not respond well to daprevir and mericitabine. Screening of patients for pre-existing resistant mutations before commencement of therapy and monitoring during and after therapy are recommended.


Subject(s)
Humans , Male , Female , Hepacivirus , HIV Infections
6.
文章 | IMSEAR | ID: sea-223134

摘要

Background: Generalized pustular psoriasis (GPP) is a chronic disease associated with genetic factors related to mutations of the interleukin 36 receptor antagonist gene (IL36RN) and the caspase recruitment domain 14 gene (CARD14). However, the relevance of these mutations to the clinical features and severity of GPP remains unclear. Aims: Our objective was to correlate the presence of IL36RN and CARD14 mutations with the clinical and laboratory findings in patients with GPP. Methods: This cross-sectional descriptive study was conducted in 64 subjects with GPP. Clinical manifestations were recorded and the severity was graded as mild, moderate, or severe. Routine laboratory tests were performed and blood samples were collected for Sanger sequencing. The clinical data of patients were compared among the different mutation groups. Results: The two main variants of IL36RN were c.115+6T > C (p.Arg10ArgfsX1) and c.227C > T (p.Pro76Leu). The major CARD14 mutations were c.2458C > T (p.Arg820Trp), c.1641C > T (p.Arg547Ser), and c.1753G > A transitions. Provocative factors were uncommon in the group with both IL36RN and CARD14 mutations. Drugs (unspecified), especially herbals, were the most common triggers. A history of psoriasis was frequent in patients with only CARD14 mutations, but fever was uncommon. The c.1641C > T mutation was associated with leukocytosis > 15000/mm3 and the c.1753G > A mutation was associated with hypoalbuminemia <3.8g/dL. Both the c.115+6T > C and c.227C > T variants of IL36RN were associated with fever ?38.5°C while the c.115+6T > C variant was also associated with geographic tongue. No gene mutations were associated with the total severity and severity grades. Limitations: Four patients without the two major IL36RN mutations were excluded from the study. Conclusion: The presence of IL36RN and CARD14 mutations were associated with a history of psoriasis, various provocative factors, fever, leukocytosis, hypoalbuminemia, and geographic tongue. Further studies to explore the role of these mutations in therapeutic efficacy and disease outcomes are necessary.

7.
文章 在 中文 | WPRIM | ID: wpr-998959

摘要

Objective To investigate the correlation between ITPKB mutation's variant allele frequency (VAF) and prognosis of diffuse large B-cell lymphoma (DLBCL). Methods This study included 155 patients with DLBCL initially diagnosed in the People's Hospital of Xinjiang Uygur Autonomous Region from June 2014 to December 2020. Paraffin-embedded tumor tissue specimens were obtained, and tumor tissue DNA was extracted. A total of 475 hotspot genes including ITPKB were detected by the next generation sequencing to analyze the relationship of the VAF of high-frequency mutant gene with progression-free survival (PFS) and overall survival (OS). Results The mutation frequency of ITPKB was 18.71%. The PFS was significantly shorter in the patients with ITPKB mutations than in those without mutations (37 months vs. 108 months; HR=1.643, 95%CI: 0.920-2.934, P=0.093). The R-language based web tool was used to find the best VAF cutoff to differentiate prognosis. The patients were divided into two groups (VAF High vs. VAF Low+Wt) according to their VAF values. The optimal VAF threshold for ITPKB was 27.48% (HR=3.480, 95%CI: 1.70-7.13, P=0.00027). Multivariate Cox analysis was conducted using clinical indicators such as age, gender, COO classification, IPI, and LDH, and the results showed that PFS was associated with high ITPKB VAF (≥28%) (HR=3.592, 95%CI: 1.738-7.425, P < 0.001) which was an independent adverse predictor of PFS. Conclusion The high load of ITPKB mutation is an independent risk factor for the PFS of patients with DLBCL, and the VAF of ITPKB mutation has a prognostic predictive value for patients with DLBCL.

8.
文章 在 中文 | WPRIM | ID: wpr-987059

摘要

Objective@# To explore the pathogenic genes in a Chinese family affected by nonsyndromic tooth agenesis so as to study the pathogenesis of oligodontia.@*Methods @# Hospital ethical approval and informed consent of the patients and family members were obtained. Clinical data of the proband and close family members were collected, peripheral venous blood was collected, and DNA was extracted. Gene sequencing was performed through whole-exome sequencing, and then the screened pathogenic genes were verified by Sanger sequencing. The three-dimensional structure of the mutant proteins was analyzed and compared with the wild-type using bioinformatics tools.@*Results@#The two patients with congenital majority tooth loss in this family were cousins, and there were no other patients with congenital majority tooth loss in the family. Besides congenital multiple tooth loss, the two patients had no obvious hair abnormalities, finger/toe abnormalities, sweating abnormalities or other abnormal manifestations of ectodermal tissue. We found a mutant gene that in this family by carrying out gene sequencing of the patients and their close family members. A novel EDA (ectodysplasin A) missense mutation c.983C>T (p. Pro328Leu) was identified, which changed the encoded amino acid from proline (Pro) to leucine (Leu). Analysis of the mutation site showed that the site was highly conserved, and three-dimensional structure modeling also found that it changed the structure of EDA. @* Conclusion@#A novel EDA missense variant (c.983C>T, p.Pro328Leu) was first identified in a Chinese family with nonsyndromic tooth agenesis, extending the mutation spectrum of the EDA gene.

9.
文章 在 中文 | WPRIM | ID: wpr-986884

摘要

OBJECTIVE@#To analyze the clinicopathological features, molecular changes and prognostic factors in angioimmunoblastic T-cell lymphoma (AITL).@*METHODS@#Sixty-one cases AITL diagnosed by Department of Pathology of Peking University Cancer Hospital were collected with their clinical data. Morphologically, they were classified as typeⅠ[lymphoid tissue reactive hyperplasia (LRH) like]; typeⅡ[marginal zone lymphoma(MZL)like] and type Ⅲ [peripheral T-cell lymphoma, not specified (PTCL-NOS) like]. Immunohistochemical staining was used to evaluate the presence of follicular helper T-cell (TFH) phenotype, proliferation of extra germinal center (GC) follicular dendritic cells (FDCs), presence of Hodgkin and Reed-Sternberg (HRS)-like cells and large B transformation. The density of Epstein-Barr virus (EBV) + cells was counted with slides stained by Epstein-Barr virus encoded RNA (EBER) in situ hybridization on high power field (HPF). T-cell receptor / immunoglobulin gene (TCR/IG) clonality and targeted exome sequencing (TES) test were performed when necessary. SPSS 22.0 software was used for statistical analysis.@*RESULTS@#Morphological subtype (%): 11.4% (7/61) cases were classified as type Ⅰ; 50.8% (31/61) as type Ⅱ; 37.8% (23/61) as type Ⅲ. 83.6% (51/61) cases showed classical TFH immunophenotype. With variable extra-GC FDC meshwork proliferation (median 20.0%); 23.0% (14/61) had HRS-like cells; 11.5% (7/61) with large B transformation. 42.6% (26/61) of cases with high counts of EBV. 57.9% (11/19) TCR+/IG-, 26.3% (5/19) TCR+/IG+, 10.5% (2/19) were TCR-/IG-, and 5.3% (1/19) TCR-/IG+. Mutation frequencies by TES were 66.7% (20/30) for RHOA, 23.3% (7/30) for IDH2 mutation, 80.0% (24/30) for TET2 mutation, and 33.3% (10/30) DNMT3A mutation. Integrated analysis divided into four groups: (1) IDH2 and RHOA co-mutation group (7 cases): 6 cases were type Ⅱ, 1 case was type Ⅲ; all with typical TFH phenotype; HRS-like cells and large B transformation were not found; (2) RHOA single mutation group (13 cases): 1 case was type Ⅰ, 6 cases were type Ⅱ, 6 cases were type Ⅲ; 5 cases without typical TFH phenotype; 6 cases had HRS-like cells, and 2 cases with large B transformation. Atypically, 1 case showed TCR-/IG-, 1 case with TCR-/IG+, and 1 case with TCR+/IG+; (3) TET2 and/or DNMT3A mutation alone group (7 cases): 3 cases were type Ⅱ, 4 cases were type Ⅲ, all cases were found with typical TFH phenotype; 2 cases had HRS-like cells, 2 cases with large B transformation, and atypically; (4) non-mutation group (3 cases), all were type Ⅱ, with typical TFH phenotype, with significant extra-GC FDC proliferation, without HRS-like cells and large B transformation. Atypically, 1 case was TCR-/IG-. Univariate analysis confirmed that higher density of EBV positive cell was independent adverse prognostic factors for both overall survival (OS) and progression free survival(PFS), (P=0.017 and P=0.046).@*CONCLUSION@#Pathological diagnoses of ALTL cases with HRS-like cells, large B transformation or type Ⅰ are difficult. Although TCR/IG gene rearrangement test is helpful but still with limitation. TES involving RHOA, IDH2, TET2, DNMT3A can robustly assist in the differential diagnosis of those difficult cases. Higher density of EBV positive cells counts in tumor tissue might be an indicator for poor survival.


Subject(s)
Humans , Epstein-Barr Virus Infections/genetics , Herpesvirus 4, Human/genetics , T-Lymphocytes, Helper-Inducer/pathology , Immunoblastic Lymphadenopathy/pathology , Lymphoma, T-Cell, Peripheral/pathology , Receptors, Antigen, T-Cell
10.
Journal of Experimental Hematology ; (6): 1804-1810, 2023.
文章 在 中文 | WPRIM | ID: wpr-1010041

摘要

OBJECTIVE@#To investigate the gene mutation and genotype distribution of thalassemia in the population of childbearing age in Chongzuo area of Guangxi.@*METHODS@#Six α-thalassemia and 17 β-thalassemia gene mutations common in Chinese were detected by gap-polymerase chain reaction (gap-PCR) combined with agarose gel eletrophoresis and reserve dot bolt hybridization in 29 266 cases of child-bearing age suspected of thalassemia.@*RESULTS@#A total of 19 128 (65.36%) cases were identified with thalassemia. The detection rate of α-thalassemia, β-thalassemia and α-combining β-thalassemia was 45.25% (13 242/29 266), 15.47% (4 526/29 266) and 4.65% (1 360/29 266), respectively. A total carrying rate of 8 kinds of α-thalassemia gene mutations was 26.74% (15 649/58 532), including 12.51% for --SEA, followed by 5.70% for -α3.7, and 0.24% for --Thai. Among 32 α-thalassemia genotypes, the most common five were --SEA/αα, -α3.7/αα, αCSα/αα, -α4.2/αα and αWSα/αα, accounting for 47.27%, 18.31%, 8.56%, 8.52% and 7.91%, respectively, as well as 0.97% for --Thai/αα. A total carrying rate of 13 kinds of β-thalassemia gene mutations was 10.07% (5 897/58 532), including 3.63% for CD41-42, followed by 2.55% for CD17, and 0.003% for -50 (G>A). Among 17 β-thalassemia genotypes, the most common six were CD41-42/N, CD17/N, CD71-72/N, CD26/N, 28/N and IVSI-1/N, accounting for 36.15%, 25.81%, 9.43%, 8.18%, 8.09% and 7.75%. The homozygous genotype CD26/CD26 [hemoglobin (Hb): 121 g/L] and -28/-28 (Hb: 56 g/L) were respectively detected in one case, and double heterozygous genotype were detected in 5 cases, including 3 cases of CD41-42/CD26 (Hb: 41 g/L, 51 g/L, 63 g/L, respectively), 1 case of -28/IVSI-1 (Hb: 53 g/L), and 1 case of CD71-72/CD26 (Hb: 89 g/L), in which patients with moderate or severe anemia had a history of blood transfusion. Among 104 α-combining β-thalassemia genotypes, the most common were --SEA/αα, -α3.7/αα combining CD41-42/N and --SEA/αα combining CD17/N, accounting for 12.13%, 9.63% and 9.26%, respectively. In addition, 1 case of --SEA/-α3.7 combining -28/IVSI-1 (Hb: 83 g/L) and 1 case of -α3.7/αα combining CD41-42/ CD41-42 (Hb: 110 g/L) were detected without history of blood transfusion, while 1 case of αWSα/αα combining CD41-42/CD17 (Hb: 79 g/L) and 1 case of --SEA/αα combining CD17/-28 (Hb: 46 g/L) were detected with history.@*CONCLUSIONS@#The detection rate of thalassemia genes is high and the mutations are diverse in the population of childbearing age in Chongzuo area of Guangxi. The common deletion genotype is --SEA/αα in α-thalassemia and CD41-42/N in β-thalassemia, and deletion genotype --Thai is not rare. There is a certain incidence of intermediate and severe β-thalassemia, and most patients require transfusion therapy. The results are beneficial for genetic consultation and intervention of thalassemia.


Subject(s)
Humans , beta-Thalassemia/genetics , alpha-Thalassemia/genetics , Dipeptidyl Peptidase 4/genetics , China/epidemiology , Genotype , Mutation
11.
文章 在 中文 | WPRIM | ID: wpr-982083

摘要

OBJECTIVE@#To investigate the clinical characteristics, prognostic factors and efficacy of hypomethylating agent (HMA) in patients with chronic myelomonocytic leukemia (CMML).@*METHODS@#The clinical data of 37 newly diagnosed patients with CMML was analyzed retrospectively, and their clinical characteristics and the efficacy of HMA were summarized. Kaplan-Meier and Log-rank test were used for univariate survival analysis, and Cox proportional hazards regression model was used for multivariate analysis.@*RESULTS@#The median age at diagnosis was 67 years old. Their common manifestations included fatigue, bleeding, abnormal blood routine and fever. Most patients had splenomegaly. According to FAB classification, there were 6 cases of myelodysplastic CMML and 31 cases of myeloproliferative CMML, while according to WHO classification, 8 patients belonged to CMML-0, 9 patients to CMML-1 and 20 patients to CMML-2. At the time of diagnosis, the median white blood cell count was 32.84×109/L, median hemoglobin (Hb) was 101 g/L, median platelet count was 65×109/L, median absolute monocyte count was 9.53×109//L, median absolute neutrophil count (ANC) was 11.29×109//L and median lactate dehydrogenase (LDH) was 374 U/L. Cytogenetic abnormalities were found in 4 cases among the 31 patients who underwent karyotype analysis or fluorescence in situ hybridization detection. There were 12 patients who had analyzable results and gene mutations were identified in 11 cases, including ASXL1, NRAS, TET2, SRSF2 and RUNX1. Among the 6 patients who were treated with HMA and could be evaluated for efficacy, 2 patients achieved complete remission, 1 patient achieved partial remission and 2 patients achieved clinical benefit. Compared with the non-HMA treatment group, overall survival (OS) time was not significantly prolonged in the HMA treatment group. Univariate analysis showed that Hb<100 g/L, ANC≥12×109/L, LDH≥250 U/L and peripheral blood (PB) blasts ≥5% were significantly associated with poor OS, while WHO classification CMML-2, Hb<100 g/L, ANC≥12×109/L, LDH≥250 U/L and PB blasts≥5% were significantly associated with poor leukemia-free survival (LFS) (P<0.05). Multivariate analysis showed that ANC≥12×109/L and PB blasts≥5% were significantly associated with poor OS and LFS (P<0.05).@*CONCLUSION@#CMML has high heterogeneity in clinical characteristics, genetic changes, prognosis and treatment response. HMA can not significantly improve the survival of CMML patients. ANC≥12×109/L and PB blasts≥5% are independent prognostic factors of OS and LFS in patients with CMML.


Subject(s)
Humans , Aged , Leukemia, Myelomonocytic, Chronic/genetics , Retrospective Studies , In Situ Hybridization, Fluorescence , Survival Analysis , Prognosis
12.
文章 在 中文 | WPRIM | ID: wpr-982073

摘要

OBJECTIVE@#To investigate the mutational spectrum in young patients with diffuse large B-cell lymphoma (DLBCL) based on next generation sequencing (NGS), and to provide a basis for in-depth understanding of the molecular biological characteristics and accurate prognosis of young DLBCL.@*METHODS@#From March 2009 to March 2021, 68 young DLBCL patients with complete initial diagnosis data from the Department of Hematology, The People's Hospital Xinjiang Uygur Autonomous Region were retrospectively analyzed, and their paraffin-embedded tissues were subjected to targeted sequencing analysis by NGS technology (including 475 Target genes), and the differences in gene mutation profiles and signaling pathways between high-risk patients with aaIPI ≥2 and low-intermediate risk patients with aaIPI <2 were compared.@*RESULTS@#A total of 44 high-frequency mutation genes were detected in 68 young DLBCL patients. By comparing the high-frequency mutation genes in aaIPI high-risk group and low-intermediate risk group, it was found that CARD11 mutation in aaIPI high-risk group was significantly higher than that in low-intermediate risk group (P =0.002), while MGA mutation (P =0.037) only appeared in the aaIPI high-risk group, and SPEN mutation (P =0.004) only appeared in the aaIPI low-intermediate risk group. The high-frequency mutation genes and clinical indicators of the aaIPI high-risk group were included in the survival analysis, and the results showed that TP53 (P =0.009, P =0.027), POU2AF1 (P =0.003, P =0.006) and CCND3 (P =0.040, P =0.014) genes mutations were associated with worse PFS and OS, while B2M was associated with better PFS (P =0.014) and OS (P =0.013). Multivariate COX regression analysis showed that the TP53, POU2AF1 and CCND3 were independent risk factors for PFS(P =0.021,P =0.005,P =0.020) and OS(P =0.042,P =0.010,P =0.013).@*CONCLUSION@#The aaIPI staging combination with molecular biology markers is more conducive to accurately judging the prognosis of young DLBCL patients. TP53, POU2AF1 and CCND3 mutations predict worse survival in the patients with the aaIPI high-risk group.


Subject(s)
Humans , Retrospective Studies , Prognosis , Lymphoma, Large B-Cell, Diffuse/genetics , Biomarkers , Mutation , High-Throughput Nucleotide Sequencing
13.
文章 在 英语 | WPRIM | ID: wpr-982039

摘要

A 24-year-old male was admitted due to recurrent redness, swelling, fever and pain in the ankle, frequently accompanied by hungry feeling. Dual energy CT scans showed multiple small gouty stones in the posterior edge of the bilateral calcaneus and in the space between the bilateral metatarsophalangeal joints. The laboratory examination results indicated hyperlipidemia, high lactate lipids, and low fasting blood glucose. Histopathology of liver biopsy showed significant glycogen accumulation. The results of gene sequencing revealed the compound heterozygous mutations of the G6PC gene c.248G>A (p.Arg83His) and c.238T>A (p.Phe80Ile) in the proband. The c.248G>A mutation was from mother and the c.238T>A mutation was from father. The diagnosis of glycogen storage disease type Ⅰa was confirmed. After giving a high starch diet and limiting monosaccharide intake, as well as receiving uric acid and blood lipids lowering therapy, the condition of the patient was gradually stabilized. After a one-year follow-up, there were no acute episodes of gout and a significant improvement in hungry feeling in the patient.


Subject(s)
Male , Humans , Young Adult , Adult , Glycogen Storage Disease Type I/genetics , Gout/genetics , Mutation , Lipids
14.
文章 在 英语 | WPRIM | ID: wpr-982038

摘要

Two male patients with bifid rib-basal cell nevus-jaw cyst syndrome (BCNS) were admitted to Department of Stomatology, the First Affiliated Hospital of Bengbu Medical College due to radiological findings of multiple low density shadows in the jaw. Clinical and imaging findings showed thoracic malformation, calcification of the tentorium cerebellum and falx cerebrum as well as widening of the orbital distance. Whole exon high-throughput sequencing was performed in two patients and their family members. The heterozygous mutations of c.C2541C>A(p.Y847X) and c.C1501C>T(p.Q501X) in PTCH1 gene were detected in both patients. Diagnosis of BCNS was confirmed. The heterozygous mutations of PTCH1 gene locus were also found in the mothers of the two probands. Proband 1 showed clinical manifestations of low intelligence, and heterozygous mutations of c.C2141T(p.P714L) and c.G3343A(p.V1115I) were detected in FANCD2 gene. Proband 2 had normal intelligence and no FANCD2 mutation. The fenestration decompression and curettage of jaw cyst were performed in both patients. Regular follow-up showed good bone growth at the original lesion, and no recurrence has been observed so far.


Subject(s)
Humans , Male , Basal Cell Nevus Syndrome/diagnosis , Mutation , Nevus , Patched-1 Receptor/genetics , Pedigree , Ribs/abnormalities
15.
文章 在 中文 | WPRIM | ID: wpr-982019

摘要

OBJECTIVES@#To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM).@*METHODS@#A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data.@*RESULTS@#Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05).@*CONCLUSIONS@#There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.


Subject(s)
Male , Female , Humans , Child , Stroke Volume , Retrospective Studies , Ventricular Function, Left , Phenotype , Cardiomyopathy, Dilated/diagnosis , Mutation , ATPases Associated with Diverse Cellular Activities/genetics , Membrane Proteins/genetics , Mitochondrial Proteins/genetics
16.
文章 在 中文 | WPRIM | ID: wpr-981974

摘要

Hypertrophic cardiomyopathy (HCM) is the most common monogenic inherited myocardial disease in children, and mutations in sarcomere genes (such as MYH7 and MYBPC3) are the most common genetic etiology of HCM, among which mutations in the MYH7 gene are the most common and account for 30%-50%. MYH7 gene mutations have the characteristics of being affected by environmental factors, coexisting with multiple genetic variations, and age-dependent penetrance, which leads to different or overlapping clinical phenotypes in children, including various cardiomyopathies and skeletal myopathies. At present, the pathogenesis, course, and prognosis of HCM caused by MYH7 gene mutations in children remain unclear. This article summarizes the possible pathogenesis, clinical phenotype, and treatment of HCM caused by MYH7 gene mutations, in order to facilitate the accurate prognostic evaluation and individualized management and treatment of the children with this disorder.


Subject(s)
Child , Humans , Cardiomyopathy, Hypertrophic/therapy , Phenotype , Troponin T/genetics , Mutation , Carrier Proteins/genetics , Myosin Heavy Chains/genetics , Cardiac Myosins/genetics
17.
Asian Journal of Andrology ; (6): 350-355, 2023.
文章 在 英语 | WPRIM | ID: wpr-981954

摘要

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenozoospermia categorized by immotile spermatozoa with abnormal flagella in ejaculate. Whole-exome sequencing (WES) is used to detect pathogenic variants in patients with MMAF. In this study, a novel homozygous frameshift variant (c.6158_6159insT) in dynein axonemal heavy chain 8 (DNAH8) from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed DNAH8 mRNA decay in these patients with the DNAH8 mutation. Hematoxylin-eosin staining and transmission electron microscopy revealed highly divergent morphology and ultrastructure of sperm flagella in these patients. Furthermore, an immunofluorescence assay showed the absence of DNAH8 and a reduction in its associated protein DNAH17 in the patients' spermatozoa. Collectively, our study expands the phenotypic spectrum of patients with DNAH8-related MMAF worldwide.


Subject(s)
Humans , Male , Consanguinity , Pakistan , Infertility, Male/metabolism , Semen/metabolism , Sperm Tail/metabolism , Spermatozoa/metabolism , Flagella/pathology , Mutation
18.
Cancer Research and Clinic ; (6): 361-365, 2023.
文章 在 中文 | WPRIM | ID: wpr-996239

摘要

Objective:To explore KRAS, NRAS, BRAF gene mutations and microsatellite instability(MSI) in colorectal cancer tissues as well as their correlation with the clinicopathological characteristics of patients.Methods:The clinicopathological data of 473 colorectal cancer patients in Shanxi Province Cancer Hospital from October 2020 to May 2021 were retrospectively analyzed. The mutation status of KRAS, NRAS and BRAF gene in the paraffin tissues were detected by using amplification refractory mutation system (ARMS) method. Polymerase chain reaction (PCR)-capillary electrophoresis was used to analyze MSI status, and the correlation of the clinicopathological characteristics of patients with gene mutations and MSI status was analyzed.Results:The mutation rates of KRAS, NRAS and BRAF were 45.03% (213/473), 2.96% (14/473) and 5.50% (26/473), respectively in 473 patients with colorectal cancer. No case harbored both 2 gene mutations was detected. The mutation rate of KRAS gene in well differentiated adenocarcinoma was higher than that in poorly differentiated adenocarcinoma [47.4% (175/369) vs. 36.5% (38/104), χ2 = 3.89, P = 0.049]. NRAS mutation rate in female was higher than that in male [5.0% (10/202) vs. 1.5% (4/271), χ2 = 4.86, P = 0.027], and the NRAS mutation rate in patients with tumor diameter ≤ 3 cm was higher than that in those with tumor diameter >3 cm [7.1% (7/98) vs. 1.9% (7/375), P = 0.013]. BRAF mutation rate of tumors located in colon was higher than that in rectum [11.7% (20/171) vs.2.0% (6/302), χ2 = 19.81, P < 0.001]; BRAF mutation rate in poorly differentiated tumor was higher than that in well differentiated tumor [10.6% (11/104) vs. 4.1% (15/369), χ2 = 6.62, P = 0.010]; BRAF mutation rate in patients with mucus was higher than that in those without mucus [10.9% (11/101) vs. 4.0% (15/372), χ2 = 7.19, P = 0.007]; BRAF mutation rate in patients with lymphatic metastasis was higher than that in patients without lymphatic metastasis [8.2% (15/182) vs.3.8% (11/291), χ2 = 4.29, P = 0.038]. The incidence of high frequency MSI (MSI-H) in 473 colorectal cancer tissues was 7.19% (34/473). The incidence of MSI-H in colon was higher than that in rectum [14.0% (24/171) vs. 3.3% (10/302), χ2 = 18.82, P < 0.001]; the incidence of MSI-H in patient with poor differentiated tumor was higher than that in those with well differentiated tumor [17.3% (18/104) vs. 4.3% (16/369), χ2 = 20.46, P < 0.001]; the incidence of MSI-H in patients with mucus was higher than that in those without mucus [11.9% (12/101) vs. 5.9% (22/372), χ2 = 4.24, P = 0.039]; and the incidence of MSI-H in patients without lymphatic metastasis was higher than that in patients with lymphatic metastasis [10.0% (29/291) vs. 2.7% (5/182), χ2 = 8.75, P = 0.003]. In addition, the incidence of MSI-H was on the rise in patients with BRAF mutation ( P < 0.001). Conclusions:KRAS, NRAS, BRAF gene mutations and MSI status are correlated with the clinicopathological characteristics of patients with colorectal cancer; there is a close relationship between MSI-H and BRAF mutation.

19.
文章 在 中文 | WPRIM | ID: wpr-995752

摘要

Objective:To analyze the distribution of different SF3B1 genotypes in patients with myelodysplastic syndromes (MDS) and its prognostic value.Methods:Totally, 377MDS patients who were initially diagnosed in the First Affiliated Hospital of Nanjing Medical University from January 2014 to January 2022 were included in the retrospective analysis.The patients were divided into three different groups according to mutation stcote of SF3B1, including 317 patients with SF3B1 wild type (SF3B1 WT) (214 males and 103 females, 63(49, 71) years old),39 patients with SF3B1 K700E mutation(SF3B1 K700E(17 males and 22 females, 65(52, 73)years old)) and 21 patients with SF3B1 non-K700E mutation(SF3B1 non-K700E)(13 males and 8 females, 67(63, 73) years old). MDS-related 20 gene mutations were detected using targeted sequencing technology; Survival curves were constructed by the Kaplan-Meier method; Cox proportional hazards model was established to evaluate different factors at diagnosis on survival by univariate and multivariate analyses.. Results:Compared with SF3B1 non-K700E patients, SF3B1 K700E patients had a higher median absolute neutrophil count ( P=0.002) and were likely to be in the low/int-1 International Prognostic Scoring System (IPSS) categories ( P=0.023). A 20-gene targeted sequencing analysis showed that, compared with SF3B1 WT patients, SF3B1 K700E patients were associated with lower frequency of ASXL1 and U2AF1 mutations ( P=0.018 and P=0.003); while compared with SF3B1 non-K700E patients, the frequency of ASXL1 mutation was significantly lower in SF3B1 K700E cases ( P=0.029). Patients with SF3B1 K700E had better overall survival (OS) in comparison with SF3B1 WT and SF3B1 non-K700E in MDS patients ( P<0.001 and P=0.045, respectively). In comparison with SF3B1 WT patients, SF3B1 MUT patients had more favorable OS and progression-free survival (PFS) in MDS without excess blasts ( P<0.001 and P<0.001, respectively), but no significant difference was found in MDS with excess blasts ( P>0.05). Compared with SF3B1 WT patients, SF3B1 K700E patients had superior OS and PFS in the int-1 IPSS category ( P=0.010 and P=0.013, respectively). By multivariable analysis, the presence of SF3B1 K700Ewas an independent predictor of superior OS ( HR=0.461,95% CI 0.262-0.811, P=0.007). Conclusion:SF3B1 K700E and SF3B1 non-K700E patients had significantly improved OS in comparison with SF3B1 WT MDS patients. Furthermore, SF3B1 K700E patients were associated with a better OS compared with SF3B1 non-K700E MDS patients. SF3B1 mutation could not overcome the poor prognostic effect of excess blasts, which highlights the importance of the SF3B1 mutation subtype in risk assessment of MDS without excess blasts.

20.
文章 在 中文 | WPRIM | ID: wpr-995665

摘要

Objective:To observe and determine the gene mutation site and clinical phenotype of a NDP gene mutant family, and provide a basis for the prenatal diagnosis of offspring. Methods:A pedigree investigation study. Two patients and 6 family members of a third-generation Han family with NDP gene mutation who were admitted to the Maternal and Child Health Hospital of Gansu Province from July 2019 to December 2021 were included in the study. The patients and their parents underwent the examination of pupil light reflex, strip light imaging, visual acuity evaluation, fundus color photography, and wide-field fluorescein fundus angiography (FFA). Peripheral blood of all the subjects was collected, the pathogenic genes were screened by whole exome sequencing, and NDP genes were detected by amplification of multiple ligated probes. DNA prenatal diagnosis was performed by amniocentesis at 19th weeks of the mother's third gestation. Results:Proband (Ⅲ1), male, 4 years old, full term natural delivery. At about 40 days after birth, B-mode ultrasonography indicated total retinal detachment in both eyes. Normal hearing and intelligence. Fundus examination was not performed. First sibling of proband (Ⅲ2, big younger brother), ophthalmologic examination 30 days after birth, retinal detachment in both eyes. Proband's mother (Ⅱ2) had unvascularized peripheral temporal retina in both eyes. Wide-angle FFA examination showed no vascularization of the peripheral temporal retina in both eyes, and slight leakage of peripheral vascular fluorescein. The proband's second sibling (Ⅲ3, little younger brother) was screened for neonatal eye disease 1 day after birth. No abnormalities were observed outside both eyes. Cornea and lens transparent. No abnormalities were observed in the optic disc and macula in both eyes. No vascular curvature was observed in the peripheral retina. The results of gene detection showed that there was hemizygote deletion in exon 2 of NDP gene of the proband (Ⅲ1) and its big younger brother (Ⅲ2). His mother (Ⅱ2) had heterozygosity deletion in exon 2 of NDP gene. The phenotype and genetic test results of the proband's father (Ⅱ1), uncle (Ⅱ3), maternal grandfather (Ⅰ1) and maternal grandmother (Ⅰ2) were not abnormal. Conclusions:The hemizygote deletion in exon 2 of NDP gene is a pathogenic variation in the native family. The clinical phenotypes of different genders are different. Prenatal diagnosis is an effective way to block hereditary diseases in families.

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